The overall goal of the proposed project is to gain a better understanding of the neural mechanisms governing the regulation of rage and aggressive behavior. The basic objective of this proposal is to identify the neuroanatomical, neurochemical and behavioral properties of two functionally different pathways that control defensive rage behavior in the cat: one pathway is critical for the expression of this response and the other modulates it. Four hypotheses are proposed. The first hypothesis states that an excitatory amino acid (EAA) pathway, arising from the medial hypothalamus, constitutes the principal link to the midbrain periaqueductal gray (PAG) where it interacts with NMDA receptors to elicit defensive rage behavior. Hypotheses 2-4 concern pathways that modulate defensive rage. The second hypothesis is that a different EAA pathway that arises from the basomedial complex of amygdala facilitates defensive rage by acting upon EAA receptors in the PAG. A third hypothesis is that excitatory pathways arising from the medial nucleus of amygdala and bed nucleus of the stria terminal is use substance P as their neurotransmitter to facilitate defensive rage at the level of the medial hypothalamus. A fourth hypothesis is that the central nucleus of amygdala suppresses defensive rage behavior by virtue of its inhibitory, enkephalinergic projections to the PAG. These hypotheses will be tested by employing a number of different but converging approaches. These include: (a) an analysis of the effects of amygdaloid (or hypothalamic) stimulation upon elicited defensive rage behavior and the effects of focal drug infusion in blocking such effects; (b) retrograde and immunocytochemical labelling of amygdaloid and hypothalamic neurons associated with defensive rage; (c) receptor autoradiography of PAG and medial hypothalamic defensive rage sites; and (d) in vivo microdialysis of EAA release at PAG defensive rage sites following medial hypothalamic or basal amygdaloid stimulation. New insights obtained from these studies can provide the bases for better strategies to be used for the development of drugs that may act at selective brain sites for the treatment of aggressive disorders and related forms of emotional dysfunction.